Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

Cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) are both greatly important metabolic enzymes in various tissues, including brain. Although expressions of brain CYPs and UGTs and their contributions to drug disposition are much less than liver, both CYPs and UGTs also mediate metabolism of endogenous substances including dopamine and serotonin as well as some drugs such as morphine in brain, demonstrating their important roles in maintenance of brain homeostasis or pharmacological activity of drugs. Some diseases such as epilepsy, Parkinson’s disease and Alzheimer’s disease are often associated with the alterations of CYPs and UGTs in brain, which may be involved in processes of these diseases via disturbing metabolism of endogenous substances or resisting drugs. This article reviewed the alterations of CYPs and UGTs in brain, the effects on endogenous substances and drugs and their clinical significances. Understanding the roles of CYPs and UGTs in brain provides some new strategies for the treatment of central nervous system diseases.

A widely distributed metalloenzyme class enables gut microbial metabolism of host- and diet-derived catechols

Catechol dehydroxylation is a central chemical transformation in the gut microbial metabolism of plant- and host-derived small molecules. However, the molecular basis for this transformation and its distribution among gut microorganisms are poorly understood. Here, we characterize a molybdenum-dependent enzyme from the human gut bacterium Eggerthella lenta that dehydroxylates catecholamine neurotransmitters. Our findings suggest that this activity enables E. lenta to use dopamine as an electron acceptor. We also identify candidate dehydroxylases that metabolize additional host- and plant-derived catechols. These dehydroxylases belong to a distinct group of largely uncharacterized molybdenum-dependent enzymes that likely mediate primary and secondary metabolism in multiple environments. Finally, we observe catechol dehydroxylation in the gut microbiotas of diverse mammals, confirming the presence of this chemistry in habitats beyond the human gut. These results suggest that the chemical strategies that mediate metabolism and interactions in the human gut are relevant to a broad range of species and habitats.

A widely distributed metalloenzyme class enables gut microbial metabolism of host- and diet-derived catechols

Catechol dehydroxylation is a central chemical transformation in the gut microbial metabolism of plant- and host-derived small molecules. However, the molecular basis for this transformation and its distribution among gut microorganisms are poorly understood. Here, we characterize a molybdenum-dependent enzyme from the prevalent human gut bacteriumEggerthella lentathat specifically dehydroxylates catecholamine neurotransmitters available in the human gut. Our findings suggest that this activity enablesE. lentato use dopamine as an electron acceptor under anaerobic conditions. In addition to characterizing catecholamine dehydroxylation, we identify candidate molybdenum-dependent enzymes that dehydroxylate additional host-and plant-derived small molecules. These gut bacterial catechol dehydroxylases are specific in their substrate scope and transcriptional regulation and belong to a distinct group of largely uncharacterized molybdenum-dependent enzymes that likely mediate both primary and secondary metabolism in multiple environments. Finally, we observe catechol dehydroxylation in the gut microbiotas of diverse mammals, suggesting that this chemistry is present in habitats beyond the human gut. Altogether, our data reveal the molecular basis of catechol dehydroxylation among gut bacteria and suggest that the chemical strategies that mediate metabolism and interactions in the human gut are relevant to a broad range of species and habitats.

Rapid shift in substrate utilization driven by hypothalamic Agrp neurons

Agrp neurons drive feeding. To what extend these neurons participate in the regulation of other homeostatic processes is not well understood. We investigated the role of Agrp neurons in substrate utilization in mice. Activation of Agrp neurons was sufficient to rapidly increase RER and carbohydrate utilization, while decreasing fat utilization. These metabolic changes were linearly correlated with carbohydrates ingested, but not protein or fat ingestion. However, even in the absence of ingestive behaviors, activation of Agrp neurons led to changes in substrate utilization in well-fed mice. These effects were coupled to metabolic shifts towards lipogenesis. Inhibition of fatty acid synthetase (FAS) blunted the effects of Agrp neurons on substrate utilization. Finally, Agrp neurons controlled peripheral metabolism, but not food intake, via ß3-adrenergic receptor signaling in fat tissues. These results reveal a novel component of Agrp neuron-mediate metabolism regulation that involves sympathetic activity on fat compartments to shift metabolism towards lipogenesis.

Proximal Tubule Cell Hypothesis for Cardiorenal Syndrome in Diabetes

Incidence of cardiovascular disease (CVD) is remarkably high among patients with chronic kidney disease (CKD), even in the early microalbuminuric stages with normal glomerular filtration rates. Proximal tubule cells (PTCs) mediate metabolism and urinary excretion of vasculotoxic substances via apical and basolateral receptors and transporters. These cells also retrieve vasculoprotective substances from circulation or synthesize them for release into the circulation. PTCs are also involved in the uptake of sodium and phosphate, which are critical for hemodynamic regulation and maintaining the mineral balance, respectively. Dysregulation of PTC functions in CKD is likely to be associated with the development of CVD and is linked to the progression to end-stage renal disease. In particular, PTC dysfunction occurs early in diabetic nephropathy, a leading cause of CKD. It is therefore important to elucidate the mechanisms of PTC dysfunction to develop therapeutic strategies for treating cardiorenal syndrome in diabetes.

Regulation of Cellular Metabolism and Cytokines by the Medicinal Herb Feverfew in the Human Monocytic THP-1 Cells

The herb feverfew is a folk remedy for various symptoms including inflammation. Inflammation has recently been implicated in the genesis of many diseases including cancers, atherosclerosis and rheumatoid arthritis. The mechanisms of action of feverfew in the human body are largely unknown. To determine the cellular targets of feverfew extracts, we have utilized oligo microarrays to study the gene expression profiles elicited by feverfew extracts in human monocytic THP-1 cells. We have identified 400 genes that are consistently regulated by feverfew extracts. Most of the genes are involved in cellular metabolism. However, the genes undergoing the highest degree of change by feverfew treatment are involved in other pathways including chemokine function, water homeostasis and heme-mediated signaling. Our results also suggest that feverfew extracts effectively reduce Lipopolysaccharides (LPS)-mediated TNF-α and CCL2 (MCP-1) releases by THP-1 cells. We hypothesize that feverfew components mediate metabolism, cell migration and cytokine production in human monocytes/macrophages.

DELETIONS GENERATED BY THE TRANSPOSON Tn10 IN THE srl recA REGION OF THE ESCHERICHIA COLI K-12 CHROMOSOME

ABSTRACT A negative regulatory gene for the srl operon (srlR) was recognized by the characteristics of an insertion mutation generated by the transposon TnlO determining tetracycline resistance. This finding is discussed in light of previous hypotheses on the regulation of the srl genes, which mediate metabolism of glucitol (i.e, sorbitol). Mapping showed that the order of genes in this region is: srlR srlD srlC recA alaS. Using two different methods, five mutations of both srl and recA were detected. The phenotype conferred by these mutations, UV sensitivity and extreme recombination deficiency, is characteristic of standard recA point mutants. Three of the mutations were deletions that also removed the genes for tetracycline resistance of the nearby transposon. A fourth mutation ended at a distance from Tn10 sufficient to allow separation of the two by recombination following P1 transduction; our tests did not allow US to conclude whether this mutation was an inversion or a deletion. The fifth mutation was a deletion that seemed to end immediately adjacent to the boundary of Tn10. proximal to recA. Mechanisms for the generaticn of these srl recA mutations are discussed.